Pancreatic cancer is one of the most aggressive and devastating human disease. Almost all patients diagnosed with the disease die from the malignancy with a medium survival of less than six months. Clinically, the disease often evades detection during its early stages due to the lack of specific symptoms and limitation in diagnostic methods. Adding to this problem, pancreatic cancer is resistance to most forms of treatments such as chemotherapy, radiation, and combination therapy. One single most important cause for such a dismal clinic prognosis of pancreatic cancer is the lack of fundamental understanding of basic biology of human pancreas both under physiological and pathophysiological conditions. A recent study by the National Cancer Institute Pancreatic Cancer Progress Review Group concluded that pancreatic cancer is disproportionately underrepresented in both clinical and basic research compared with other cancer sites. Although many of the genetic changes associated with pancreatic cancer development have been revealed, significant gaps exist in our understanding of how these genetic alterations lead to the initiation, development, and maintenance of pancreatic cancer. This information is essential for develop new and effective diagnostics and treatments for pancreatic cancer. One major roadblock for pancreatic cancer research is the lack of genetically tractable human cancer cell model systems to investigate the origins and progression of pancreatic cancer. To overcome this barrier, we have recently developed a genetically defined human pancreatic cancer cell model using genetic components known to be frequently altered in pancreatic cancer. We will use our genetically defined human pancreatic cancer model to screen chemical libraries for the purpose of discovering of chemical compounds that preferentially kill the cancer cells but not normal human pancreatic cells. These studies may lead to the identification of potential novel and effective treatments for pancreatic cancer. In addition, the identification of such mechanism-based chemical inhibitors will also aid the elucidation of down-stream signaling pathways of these well-defined genetic alterations that are important for the initiation and development of this destructive disease. [unreadable] [unreadable]